Pain represents a major health and economic problem throughout the world. Despite advances in understanding the physiological basis of pain, an ideal analgesic has yet to be discovered. Among analgesic drugs, the opioid class of compounds is widely used for pain treatment. The opioid drugs produce effects by interacting with the opioid receptors. The existence of at least three opioid receptor types, μ (mu), δ (delta), and κ (kappa) has been established. All three opioid receptor types are located in the human peripheral and central nervous system, and each has a role in the mediation of pain.
Opioid compounds have opium or morphine-like properties and are primarily used to treat pain, but may have other pharmacological effects including drowsiness, respiratory depression, and constipation, as well as abuse potential and tolerance. Opioid agonists include compounds that bind to an opioid receptor thereby forming a complex which elicits pharmacological responses particular to the nature of the receptor. Kappa (.kappa.)-opioid receptor agonists include compounds that induce analgesia predominantly by acting on kappa-opioid receptors. Examples of kappa-opioid agonists include nalbuphine, pentazocine, butorphanol, benzomorphan, and benzacetamide, phenothiazine, thiazine, and benzodiazepine derivatives.
Opioid antagonists include compounds that pharmacologically block or reverse all (or substantially all) the effects of opioid agonists. Non-selective opioid antagonists include those antagonists that act at least on kappa, mu, and delta opioid receptors. Opioid antagonists are generally used to reverse the effects of opioid agonist overdose and treatment of opioid addiction. Examples of opioid antagonists include naloxone, naltrexone, methylnaltrexone and nalmefene.
Morphine and related opioids currently used as analgesics produce their effect primarily through their agonist action at mu opioid receptors. The administration of these drugs is limited by significant side effects such as the development of tolerance, physical dependence, addiction liability, constipation, respiratory depression, muscle rigidity, and emesis. Kappa (κ)-type agonist-antagonist opioid analgesics (e.g. nalbuphine, pentazocine, and butorphanol) are known, but are considered weak analgesics compared to μ-opioids such as morphine or oxycodone. In addition, clinical studies have shown that kappa-type agonist-antagonist opioid analgesics (agonist-antagonists) produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. Therefore, there is a need in the art for effective analgesic compounds that do not possess anti-analgesic (e.g. pain enhancing) properties, especially in men. Provided herein are compounds and methods addressing these and other needs in the art.